CRISPR-based functional evaluation of schizophrenia risk variants

Abstract

As expanding genetic and genomic studies continue to implicate a growing list of variants contributing risk to neuropsychiatric disease, an important next step is to understand the functional impact and points of convergence of these risk factors. Here, with a focus on schizophrenia, we survey the most recent findings of the rare and common variants underlying genetic risk for schizophrenia. We discuss the ongoing efforts to validate these variants in post-mortem brain tissue, as well as new approaches to combine CRISPR-based genome engineering with patient-specific human induced pluripotent stem cell (hiPSC)-based models, in order to identify putative causal schizophrenia loci that regulate gene expression and cellular function. We consider the current limitations of hiPSC-based approaches as well as the future advances necessary to improve the fidelity of this human model. With the objective of utilizing patient genotype data to improve diagnosis and predict treatment response, the integration of CRISPR-genome engineering and hiPSC-based models represent an important strategy with which to systematically demonstrate the cell-type-specific effects of schizophrenia-associated variants.

Keywords: CRISPR; Psychiatric genetics; Schizophrenia; Stem cells.